Project Summary/Abstract Monoamine oxidase B (MAO-B) is a highly abundant protein in the brain that generates oxidative stress, removes monoamines such as dopamine and norepinephrine that support normal mood, and influences the predisposition towards apoptosis. MAO-B levels and activity are highly correlated and increase after chronic stress hormone exposure. MAO-B activity is increased in rodent brain after chronic unpredictable stress, however, MAO-B has not been studied in the most common early onset (age<45 years) major depressive disorder (MDD). Using [11C]SL25.1188 positron emission tomography, we propose to study whether MAO-B VT is elevated in key brain regions in early onset MDD during medication free major depressive episodes; (MDE; n=31), and in medication free major depressive episodes with a history of treatment resistance (n=31) as well as age matched healthy controls (from n=46). The intention is to make a convincing case that MAO-B levels are frequently elevated in key affect modulating regions during MDE, especially treatment resistant MDE. Such results could be applied to develop strategies for matching MDE cases of elevated MAO-B level towards MAO-B inhibitor treatments in the clinic through identifying low cost predictors of elevated MAO-B level (such as the clinical and RDOC measures proposed and/or additional peripheral protein or genetic biomarkers in future study).